CN101307050B - 一类噁唑取代二氢吡唑多杂环衍生物、制备方法及其用途 - Google Patents
一类噁唑取代二氢吡唑多杂环衍生物、制备方法及其用途 Download PDFInfo
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Abstract
本发明公开一类噁唑取代二氢吡唑多杂环衍生物、制备方法及其用途。本发明所提供的衍生物结构如化学式D所示,通过以下方法制备该衍生物:以取代异喹啉苯丙酮为先导,首先将其展开成转化为取代异喹啉α,β不饱和酮,再关环形成5-取代异喹啉取代二氢吡唑酮,通过引入肟结构单元,最后采用微波辅助合成的方法设计合成出一系列3-甲基噁唑-5-异喹啉取代二氢吡唑多杂环化合物。根据药物化学的原理进行结构修饰,设计并合成出抗肿瘤和杀菌作用高活性的化合物。
Description
技术领域
本发明公开了一类抗肿瘤和杀菌作用的药物:噁唑取代二氢吡唑多杂环化合物合成及其生物活性。
背景技术
吡唑类衍生物因为具有多种生物活性且高效、作用机理独特,在杀菌剂中有广泛的应用价值。像已商品化的消炎止痛药1,5-二芳基吡唑化合物celecoxib(塞来昔布),它是一种较好的环氧化酶-2(COX-2)特异性抑制剂。而且自从高效的杀菌剂pyrazofurin(吡唑呋喃菌素)被发现以来,(它具有对包括革兰氏阳性菌和革兰氏阴性菌在内的广谱的杀菌活性,研究人员设计了大量的芳基吡唑衍生物,且从中筛选出许多高抑菌活性化合物。1993年日本科学家报道化合物1-吡啶取代吡唑在200mg/L时能抑制真菌、细菌;近期Boehm小组报道了新型芳基吡唑化合物由于抑制DNA回旋酶具有较高的杀菌活性;日本的Tanitame研究小组也报道了芳基吡唑类化合物对Bacillus subtilis ATCC 6633,Escherichia coli ATCC 35218,Pseudomonas fluorescens ATCC 13525和Staphylococcus aureus ATCC 6538的优良的杀菌活性,同时证明其对DNA回旋酶具有良好的抑制活性。
噁唑是含有氮和氧原子的五元杂环化合物,在众多的具有生物活性的杂环中,噁唑由于具有包括杀菌及抗癌活性在内的多种生物活性而受到广泛关注。自从Astwood等人从各种甘蓝的种子中提取出具有抗甲状腺活性的物质2-硫代噁唑烷酮后,人们开发了许多噁唑类抗菌药物,如八十年代后期应用于临床的抗炎药苯噁洛芬(Benoxaprofe)。噁唑烷酮结构是噁唑类抗菌剂的重要结构单元,这类药物用于治疗耐多种药物的革兰氏阳性菌和结核杆菌感染,是一类新型化学全合成抗菌药。该类化合物的代表药物利奈唑酮对革兰氏阳性菌以及多重耐药的病原体抗菌活性较好,耐受性良好,目前已经成为一类新型抗菌剂。杜邦公司是最早研究开发噁唑烷酮类化合物的制药公司,发现了具有潜在应用价值的化合物;普强公司经过大量构效关系的研究,合成了两个新化合物:羟哌噁唑烷酮(eperezolid)和吗啉噁酮(linezolid)。
发明内容
本发明基于吡唑和噁唑的活性,目的在于对同时具有吡唑和噁唑的先导化合物进行结构修饰和先导优化,经过多步化学反应设计合成出了一系列噁唑取代二氢吡唑多杂环化合物,并从中筛选出抑制效果更为优良的抗癌和杀菌新药剂。该发明结合氟原子结构和物理化学方面的特点,以及杂环高效活性作用,将氟原子和杂环引入到噁唑取代二氢吡唑先导结构中,提高母体化合物的生物活性。
本发明的技术方案如下:
一类噁唑取代二氢吡唑杂环衍生物,它具有如下通式:
式中R1=2-三氟基、2,4-2氯基、2-氟基;2-硝基、氢、不同位置的含Br、I的基团;R2=2,4-2氟基、2-氟基、2-三氟甲基、2-乙烯基、2-甲氧基、氢、不同位置的含Br、I的基团;R3指的是异喹啉5、6、7位上的取代基:氢、甲氧基、甲基、硝基、氟基。
本发明是以价廉易得的取代醛、酮为先导,首先将其展开成α,β不饱和酮,再关环形成酰基芳基吡唑环,通过引入肟结构单元,最后采用新型的微波辅助合成的方法设计合成出了一系列新型的噁唑取代二氢吡唑杂环衍生物。合成路线如下:
合成路线1
式中R1=2-三氟基、2,4-2氯基、2-氟基;2-硝基、氢、不同位置的含Br、I的基团;R2=2,4-2氟基、2-氟基、2-三氟甲基、2-乙烯基、2-甲氧基、氢、不同位置的含Br、I的基团;R3指的是异喹啉5、6、7位上的取代基:氢、甲氧基、甲基、硝基、氟基。
一、目标化合物D的合成方法分为四步进行:(见合成路线1)
1.异喹啉α,β不饱和酮的合成(化合物编号为A)
将取代喹啉苯丙酮和氢碘酸(HIO3)及催化级的碳纳米管负载氧化铈纳米颗粒(CeO2/CNTs)于二甲基亚砜(DMSO)中混合加热,反应1-2h,冷却至室温,得到浅黄色固体,于无水乙醇中重结晶得到无色固体。
取代喹啉苯丙酮∶氢碘酸∶碳纳米管负载氧化铈纳米颗粒=1∶1-2∶0.05(摩尔比)
反应温度:80-100℃
反应时间:1-2h
每摩尔取代喹啉苯丙酮溶于8-15升有机溶剂中
步骤适用于所有上述取代异喹啉α,β不饱和酮的合成。
2.5-异喹啉取代二氢吡唑酮的合成(化合物编号为B)
将步骤1中合成的取代异喹啉α,β不饱和酮及水合肼于丙酸中加热至回流,反应3-4h,冷却至室温,加入大量的水,在0℃时静止过夜,析出到米黄色固体,于丙酮中重结晶得到无色固体。
异喹啉α,β不饱和酮∶水合肼=1∶2(摩尔比)
反应温度:120-150℃
反应时间:3-4h
每摩尔5-异喹啉取代二氢吡唑酮溶于8-10丙酸中
步骤适用于所有上述取代异喹啉二氢吡唑酮的合成。
3.5-异喹啉取代二氢吡唑肟的合成(化合物编号为C)
将步骤2中合成的5-取代异喹啉取代二氢吡唑酮溶于正丁醇中,加入催化剂碳酸氢钠(NaHCO3),搅拌下滴加盐酸羟胺的乙醇溶液,并加热回流,反应8-12h,冷却至室温,减压脱去溶剂,得到黄色固体,将得到的固体反复用水洗涤,干燥,于乙醇中重结晶得到无色固体。
5-异喹啉取代二氢吡唑酮∶盐酸羟胺∶碳酸氢钠=1∶1.5-2∶1.5-2(摩尔比)
反应温度:100-120℃
反应时间:8-10h
每摩尔5-异喹啉取代二氢吡唑肟溶于8-20升有机溶剂中
步骤适用于所有上述异喹啉取代二氢吡唑肟的合成。
4.3-取代噁唑-5-异喹啉取代二氢吡唑的合成(化合物编号为D)
将步骤3中合成的5-异喹啉取代二氢吡唑肟溶于N,N-二甲基甲酰胺中(DMF),加入催化量的N-甲基吗啉(NMM),在0-10℃搅拌下缓慢滴加取代苯甲酰氯的DMF溶液,并用115w的微波加热20分钟,冷却至室温,加入大量的水,0℃静止过夜,析出黑色固体,经过柱层析分离得到无色固体。
5-异喹啉取代二氢吡唑肟:取代苯甲酰氯:N-甲基吗啉=1∶2.5-3∶0.06(摩尔比)
反应温度:100-110℃
反应时间:10-20m
柱层析用的展开剂为:乙酸乙酯∶石油醚(V∶V=1∶6-10)
每摩尔5-异喹啉取代二氢吡唑肟溶于5-10升有机溶剂中
步骤适用于所有上述3-取代噁唑-5-异喹啉取代二氢吡唑的合成。
实验表明,本发明的噁唑取代二氢吡唑多杂环衍生物对鼻咽癌、乳腺癌、肝癌、肺癌和大肠癌细胞显示细胞毒性,因此本发明的噁唑取代二氢吡唑衍生物用于制备抗肿瘤药物;另外,实验表明,本发明的噁唑取代二氢吡唑多杂环衍生物对革兰氏阳性菌和革兰氏阴性菌显示优良的杀菌活性,因此本发明的噁唑取代二氢吡唑衍生物用于制备杀菌药物。
具体实施方式
实施例一:2-(1-(2-(2,4-二氟苯基)-5-甲基唑-4-基)-3-(2-(三氟甲基)苯基)-4,5-二氢-吡唑5-基)-1,2,3,4-四氢异喹啉的制备(化合物编号为1)
1.5-异喹啉α,β不饱和酮的合成
在150ml的三口瓶中,加入2-三氟甲基喹啉苯丙酮0.664g(2mmol)和氢碘酸(HIO3)0.528g(3mmol)及氧化铈纳米颗粒0.0172g(0.1mmol)负载于碳纳米管上;加入二甲基亚砜(DMSO)25ml。搅拌下加热至80-100℃,反应1-2h,冷却至室温,得到浅黄色固体,于无水乙醇中重结晶得到无色固体0.358g,产率54%,Mp 62-63℃。
2.5-异喹啉取代二氢吡唑酮的合成
在150ml的三口瓶中,加入5-异喹啉α,β不饱和酮0.662g(2mmol)和98%水合肼0.204g(4mmol)于20ml丙酸中加热至回流,反应3-4h,冷却至室温,加入250ml的水,在0℃时静止过夜,析出到米黄色固体,于丙酮中重结晶得到无色固体0.358g,产率54%,Mp 84-85℃。
3.5-异喹啉取代二氢吡唑肟的合成
在150ml的三口瓶中,加入5-异喹啉取代二氢吡唑酮0.802g(2mmol),加入催化剂碳酸氢钠0.336g(4mmol),无水乙醇20ml,搅拌下滴加0.213g(3mmol)的盐酸羟胺乙醇溶液10ml,加热回流8-10h,冷却至室温,减压脱去溶剂,得到黄色固体,将得到的固体 反复用水洗涤,干燥,于乙醇中重结晶得到无色固体0.512g,产率61%,Mp 92-94℃。
4.3-取代噁唑-5-异喹啉取代二氢吡唑的合成
在150ml的三口瓶中,加入5-异喹啉取代二氢吡唑肟0.832g(2mmol),加入0.012g(0.12mmol)N-甲基吗啉(NMM),加入N,N-二甲基甲酰胺中(DMF)20ml,在0-10℃搅拌下缓慢滴加2,4-二氟苯甲酰氯的DMF溶液8ml,并用115w的微波加热12分钟,冷却至室温,加入200ml的水,0℃静止过夜,析出黑色固体,用乙酸乙酯∶石油醚(V∶V=1∶7)作为展开剂经过柱层析分离得到无色固体0.426g,产率40%,Mp 110-111℃。
实施例二:
按上述实施例一相似的方法制备了表1及表2中所列的3-取代噁唑-5-异喹啉取代二氢吡唑衍生物。
表1.本发明中的3-甲基噁唑-5-四氢异喹啉取代二氢吡唑衍生物R基团所代表的化合物
表2.本发明中的3-甲基噁唑-5-取代异喹啉取代二氢吡唑衍生物R基团所代表的化合物
实施例三:噁唑取代二氢吡唑主要衍生物对5种人癌细胞的抑制作用
方法:MTT法。取对数生长的鼻咽癌(CNE2)细胞、乳腺癌(MCF-7)细胞、肝癌(Bel-7402)细胞、肺癌(GLC-82)细胞、大肠癌(HT-29)细胞,分别稀释成2×104个/ml,分装于96孔板(0.2ml/孔)。设5-氟尿嘧啶对照组,DMSO对照组及8个不同浓度的受测化合物,每孔10μl。各组设4个平行孔,置37℃,5%CO2中培养72h实验终止前4h打入MTT液(5mg/ml)10μl/孔,再培养4h。弃去培养液,加入DMSO 100μl/孔,混匀振荡,在570nm波长下,用美国生产的BioRad 550型酶标仪测出OD值,按下列公式计算出细胞生长抑制率(半数抑制浓度,IC50)。生长抑制率=(1-用药组平均OD值/对照组平均OD值)×100%IC50越小,此化合物的细胞毒性越大,结果见表3。
表3 噁唑取代二氢吡唑主要衍生物对5种人癌细胞的细胞毒性
结果表明:本发明所述噁唑取代二氢吡唑主要衍生物均对CNE2,MCF-7,Bel-7402,GLC-82,HT-29细胞显示出细胞毒性,部分与阳性对照5-氟尿嘧啶相当,其中,化合物4对CNE2细胞、化合物22对MCF-7细胞、化合物1对HT-29细胞的细胞毒性甚至比5-氟尿嘧啶的还要强。
实施例四:噁唑取代二氢吡唑主要衍生物的杀菌活性
杀菌活性测试方法如下:
1、待测菌液的制备:从新鲜菌种斜面沾取少量的菌苔,接种在适合实验菌生长的培养基中,细菌放在37℃的培养箱中培养18-24h。培养后加入2-3mL的无菌生理盐水,用无菌的接种针将菌体充分的洗下,用管口带棉花的无菌吸管从斜面中吸出悬液于无菌试管中,然后进行计数。细菌再用MH培养基稀释50倍,使其最终浓度为103-105cfu/mL。
2、对照:卡那霉素,青霉素
3、药敏板的制备:取无菌96孔板,于每排1号孔加入培养基100μL,作为空白对照;2-10号孔加入不同浓度的受试化合物溶液10μL和新鲜配置的菌液90μL。11号孔加入已知的对照药品10μL和菌液90μL作为阴性对照;12号孔不含受试药物,作为阳性对照。每个浓度做三个重复。
4、培养:细菌放在37℃的培养箱中培养24h后加入2mg/mL的MTT溶液50μL作用4-5h后,每孔再加入裂解液100μL异丁醇盐酸SDS)作用12h。
5、MIC值判定:将上述处理好的药敏板,用酶标分析仪在570nm下测各孔的OD值。计算IC50值,作为药物的最低抑菌浓度即MIC。抑菌活性结果见表4。
表4 噁唑取代二氢吡唑主要衍生物的杀菌活性
结果表明:本发明所述噁唑取代二氢吡唑主要衍生物对B.subtilis,S.aureus,P.fluorescens,E.coli细菌显示出比较强的杀灭活性,部分与对照青霉素和卡那霉素相当,其中,化合物34对B.subtilis细菌、化合物22,28,31,34对P.fluorescens细菌、化合物3,31对E.coli细菌的杀灭活性甚至比对照青霉和素卡那霉素的还要强。
附:1-20号化合物的熔点、高分辨质谱、核磁共振氢谱及碳谱数据
2-(1-(2-(2,4-二氟苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(1):
MP 62-63℃;ESI-MS:538.4(C29H23F5N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.62(t,2H,Isoquinoline-H),2.73(t,2H,Isoquinoline-H),2.87(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.67(t,2H,Isoquinoline-H),4.48(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.80-7.91(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.8,28.2,37.6,47.9,55.9,69.2,106.3,111.0,119.2,119.8,125.4,125.5,125.9,126.0,127.9,128.1,128.4,128.8,129.7,130.6,131.0,132.9,133.6,134.1,138.0,139.2,152.3,161.2,164.8.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(2):
MP 59-60℃;ESI-MS:520.1(C29H24F4N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.32(s,3H,Me),2.59(dd,J=18.0 and 3.0Hz,1H,pyrazole,4-Ha),2.64(t,2H,Isoquinoline-H),2.70(t,2H,Isoquinoline-H),2.88(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.62(t,2H,Isoquinoline-H),4.52(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.99-7.84(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.6,28.4,37.9,47.5,55.8,68.8,116.3,118.8,123.7,125.1,125.4,125.5,126.1,126.3,127.6,128.0,128.5,129.1,129.7,130.2,130.8,131.9,132.9,133.8,137.9,138.6,152.5,161.5,162.3.
2-(1-(2-三氟苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(3):
MP 59-60℃;ESI-MS:570.9(C30H24F6N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.35(s,3H,Me),2.51(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.65(t,2H,Isoquinoline-H),2.78(t,2H,Isoquinoline-H),2.81(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.67(t,2H,Isoquinoline-H),4.55(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.02-7.88(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.5,28.0,38.2,47.1,55.9,68.1,118.1,118.7,125.3,125.6,125.8,125.9,126.0,127.2, 127.6,128.0,128.8,129.5,129.7,129.8,129.9,131.8,132.6,133.0,133.8,133.9,137.9,138.8,152.6,161.7.
2-(1-(2-乙烯基苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(4):
MP 61-63℃;ESI-MS:528.0(C31H27F3N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.39(s,3H,Me),2.60(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.68(t,2H,Isoquinoline-H),2.71(t,2H,Isoquinoline-H),2.86(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.70(t,2H,Isoquinoline-H),4.55(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),5.50-5.66(dd,J=10.5and 1.3Hz,2H,=CH2),6.86(dd,J=17.2and 1.3Hz,1H,=CH),7.06-7.84(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.2,28.4,38.5,47.4,55.3,68.8,115.0,118.5,125.8,125.9,126.0,126.3,126.6,127.0,127.5,127.6,128.2,128.8,129.0,129.1,129.8,131.5,132.7,133.1,135.0,135.3,137.8,138.2,139.0,152.4,161.3.
2-(1-(2-甲氧基苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(5):
MP 64-65℃;ESI-MS:533.1(C30H27F3N4O2,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.47(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.72(t,2H,Isoquinoline-H),2.79(t,2H,Isoquinoline-H),2.75(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.63(t,2H,Isoquinoline-H),3.75(s,3H,OMe),4.44(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.00-7.82(m,12H,ArH);13CNMR(CDCl3,125MHz):δ5.5,27.9,37.9,48.4,55.3,57.2,69.2,112.1,114.5,118.9,121.3,125.8,125.9,126.1,126.3,127.5,127.9,128.1,128.7,128.8,129.5,130.0,131.2,132.3,134.2,137.9,140.1,152.8,157.9,160.3.
2-(3-(2,4-二氯苯基)-1-(2-(2,4-二氟苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(6):
MP 66-68℃;ESI-MS:538.8(C28H22Cl2F2N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.63(t,2H,Isoquinoline-H),2.74(t,2H,Isoquinoline-H),2.80(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.68(t,2H,Isoquinoline-H),4.59(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.70-7.81(m,10H,ArH);13C NMR(CDCl3,125MHz):δ5.1,28.0,37.3,46.8,56.2,68.7,106.1,111.8,119.8,126.1,126.3,126.6,127.0,127.3,127.9,129.3,130.8,131.1,132.8,135.6,135.7,137.9,138.5,138.7,152.9,161.0,162.5,166.1.
2-(3-(2,4-二氯苯基)-1-(2-(2-氟苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(7):
MP 64-65℃;ESI-MS:521.1(C28H23Cl2FN4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.32(s,3H,Me),2.50(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.68(t,2H,Isoquinoline-H),2.77(t,2H,Isoquinoline-H),2.84(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.64(t,2H,Isoquinoline-H),4.50(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.00-7.80(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.5,28.3,38.2,47.8,55.9,69.2,116.9,124.2,124.7,125.7,126.2,127.5,127.6,127.9,129.1,130.4,131.0,131.2,132.3,133.8,135.5,135.6,137.7,138.7,138.8,152.7,159.9,161.0.
2-(3-(2,4-二氯苯基)-1-(2-(2-三氟甲基苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(8):
MP 66-67℃;ESI-MS:571.8(C29H23Cl2F3N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.35(s,3H,Me),2.47(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.69(t,2H,Isoquinoline-H),2.75(t,2H,Isoquinoline-H),2.87(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.69(t,2H,Isoquinoline-H),4.48(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.03-7.87(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.2,28.0,37.6,47.9,55.5,69.0,118.2,125.8,126.1,126.2,127.0,127.4,127.7,128.0,128.8,129.3,130.6,130.9,132.3,132.9,133.8,134.0,136.1,136.2,137.7,138.1,138.8,152.3,160.7.
2-(3-(2,4-二氯苯基)-1-(2-(2-乙烯基苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(9):
MP 66-68℃;ESI-MS:528.4(C30H26Cl2N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.51(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.66(t,2H,Isoquinoline-H),2.77(t,2H,Isoquinoline-H),2.82(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.72(t,2H,Isoquinoline-H),4.45(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),5.48-5.60(dd,J=10.5and 1.3Hz,2H,=CH2),6.84(dd,J=17.2and 1.3Hz,1H,=CH),6.94-7.88(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.4,28.4,38.2,47.2,55.9,69.6,114.0,125.7,125.9,126.9,127.2,127.3,127.6,127.7,128.5,128.8,128.9,131.4,132.4,133.9,134.7,135.1,136.0,136.1,137.1,137.7,138.9,139.2,152.1,160.4.
2-(3-(2,4-二氯苯基)-1-(2-(2-甲氧基苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(10):
MP 67-68℃;ESI-MS:531.4(C29H26Cl2N4O2,[M+H]+);1H NMR(CDCl3,500MHz):δ2.32(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.61(t,2H,Isoquinoline-H),2.79(t,2H,Isoquinoline-H),2.80(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.70(t,2H,Isoquinoline-H),3.78(s,3H,OMe),4.51(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.02-7.80(m,11H,ArH);13CNMR(CDCl3,125MHz):δ5.5,28.0,37.8,47.8,55.5,57.1,69.3,111.8,114.5,121.2,126.1,126.3, 127.5,127.6,128.0,128.9,129.1,129.8,130.3,132.8,133.5,135.8,135.9,138.0,138.6,139.3,152.4,158.2,160.7.
2-(3-(2-氟苯基)-1-(2-(2,4-二氟基苯基)-5-甲基噁唑基-4-基-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(11):
MP 60-61℃;ESI-MS:487.2(C28H23F3N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.58(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.68(t,2H,Isoquinoline-H),2.74(t,2H,Isoquinoline-H),2.88(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.77(t,2H,Isoquinoline-H),4.57(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.69-7.88(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.2,27.7,37.7,48.1,55.8,69.0,106.6,112.5,116.2,119.4,120.1,124.8,125.8,126.2,127.3,127.7,128.9,130.9,131.2,132.4,133.8,137.6,138.5,152.8,160.2,160.5,161.2,165.6.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-(氟基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(12):
MP 57-58℃;ESI-MS:469.3(C28H24F2N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.31(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.67(t,2H,Isoquinoline-H),2.77(t,2H,Isoquinoline-H),2.81(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.63(t,2H,Isoquinoline-H),4.48(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.03-7.89(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.2,28.0,37.5,47.8,56.2,68.8,115.1,116.7,118.5,123.9,125.2,125.7,125.8,126.3,127.9,128.1,128.9,129.7,130.0,130.8,133.0,134.1,133.8,137.6,138.9,152.7,160.5,161.1.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-(三氟甲基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(13):
MP 60-61℃;ESI-MS:520.5(C29H24F4N4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.31(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.67(t,2H,Isoquinoline-H),2.77(t,2H,Isoquinoline-H),2.81(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.63(t,2H,Isoquinoline-H),4.48(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.03-7.89(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.6,27.7,38.2,48.3,56.5,69.2,116.4,118.8,119.7,125.0,125.6,125.7,126.8,127.5,127.9,128.2,129.1,130.0,130.3,131.2,132.6,132.8,134.3,134.5,137.9,139.3,152.4,160.3,161.6.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-(乙烯基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(14):
MP 59-60℃;ESI-MS:478.1(C30H27FN4O,[M+H]+);1H NMR(CDCl3,500MHz):δ2.37(s,3H, Me),2.52(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.69(t,2H,Isoquinoline-H),2.76(t,2H,Isoquinoline-H),2.84(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.68(t,2H,Isoquinoline-H),4.42(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),5.41-5.50(dd,J=10.5and 1.3Hz,2H,=CH2),6.90(dd,J=17.2and 1.3Hz,1H,=CH),7.00-7.95(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.2,28.5,38.4,48.6,56.7,69.1,114.8,116.4,119.5,124.3,125.8,125.9,126.3,126.4,127.3,127.6,127.7,128.9,129.2,129.4,130.8,133.1,134.3,134.5,134.8,137.6,139.4,152.6,160.5,161.1.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-(甲氧基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(15):
MP 61-62℃;ESI-MS:481.8(C29H27FN4O2,[M+H]+);1H NMR(CDCl3,500MHz):δ2.31(s,3H,Me),2.55(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.64(t,2H,Isoquinoline-H),2.73(t,2H,Isoquinoline-H),2.84(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.65(t,2H,Isoquinoline-H),3.75(s,3H,OMe),4.49(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),7.00-7.91(m,12H,ArH);13CNMR(CDCl3,125MHz):δ5.6,28.0,38.6,48.1,56.2,56.5,69.8,111.5,115.0,116.7,120.1,121.8,124.3,125.6,125.8,127.5,127.8,128.9,129.0,129.9,131.2,132.8,133.7,137.8,139.8,152.2,158.6,160.1,161.4.
2-(1-(2-(2,4-二氟苯基)-5-甲基噁唑基-4-基)-3-(2-硝基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(16):
MP 81-82℃;ESI-MS:516.1(C28H23F2N5O3,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.61(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.69(t,2H,Isoquinoline-H),2.70(t,2H,Isoquinoline-H),2.85(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.61(t,2H,Isoquinoline-H),4.51(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.68-8.47(m,11H,ArH);13C NMR(CDCl3,125MHz):δ5.6,27.6,36.5,47.4,56.0,68.6,105.9,112.3,119.7,122.0,125.8,126.1,126.8,127.7,128.2,129.3,131.1,131.8,133.1,134.2,136.1,137.9,138.8,149.6,152.5,160.6,161.3,165.6.
2-(1-(2-(2-氟苯基)-5-甲基噁唑基-4-基)-3-(2-硝基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(17):
MP 84-85℃;ESI-MS:513.0(C28H24FN5O4,[M+H]+);1H NMR(CDCl3,500MHz):δ2.31(s,3H,Me),2.65(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.73(t,2H,Isoquinoline-H),2.77(t,2H,Isoquinoline-H),2.88(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.68(t,2H,Isoquinoline-H),4.57(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.87-7.64(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.3,28.2,38.9,47.2,56.3,68.1,116.2,116.3,119.5,122.1,124.6,124.9,126.0,126.5,127.5,127.9,129.1,130.0,130.8,131.1,132.8,133.3,138.0,139.3,152.9,158.8,160.1,161.1.
2-(1-(2-(2-三氟甲基苯基)-5-甲基噁唑基-4-基)-3-(2-硝基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(18):
MP 87-88℃;ESI-MS:564.2(C29H24F3N5O4,[M+H]+);1H NMR(CDCl3,500MHz):δ2.38(s,3H,Me),2.60(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.71(t,2H,Isoquinoline-H),2.81(t,2H,Isoquinoline-H),2.92(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.69(t,2H,Isoquinoline-H),4.55(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.80-7.73(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.6,28.0,38.6,47.8,56.5,68.9,116.4,118.5,119.8,122.4,125.9,126.0,126.2,127.2,127.6,127.8,128.9,129.3,129.5,130.5,132.3,132.9,133.8,134.2,137.4,138.9,152.4,158.4,160.3.
2-(1-(2-(2-乙烯基苯基)-5-甲基噁唑基-4-基)-3-(2-硝基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(19):
MP 75-76℃;ESI-MS:522.4(C30H27N5O4,[M+H]+);1H NMR(CDCl3,500MHz):δ2.32(s,3H,Me),2.47(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.66(t,2H,Isoquinoline-H),2.80(t,2H,Isoquinoline-H),2.85(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.69(t,2H,Isoquinoline-H),4.58(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),5.48-5.57(dd,J=l0.5and 1.3Hz,2H,=CH2),6.88(dd,J=17.2and 1.3Hz,1H,=CH),7.03-7.70(m,12H,ArH);13C NMR(CDCl3,125MHz):δ5.7,28.5,38.2,47.5,55.9,69.3,114.0,116.8,119.3,122.6,125.8,126.4,127.0,127.2,127.4,127.7,128.5,128.9,129.1,130.7,132.8,133.8,134.3,134.7,137.5,137.9,138.9,152.4,158.1,160.6.
2-(1-(2-(2-甲氧基苯基)-5-甲基噁唑基-4-基)-3-(2-硝基苯基)-4,5-二氢吡唑-5-基)-1,2,3,4-四氢异喹啉(20)
MP 77-78℃;ESI-MS:525.1(C29H27N5O5,[M+H]+);1H NMR(CDCl3,500MHz):δ2.35(s,3H,Me),2.49(dd,J=18.0and 3.0Hz,1H,pyrazole,4-Ha),2.64(t,2H,Isoquinoline-H),2.74(t,2H,Isoquinoline-H),2.87(dd,J=18.0and 11.0Hz,pyrazole,1H,4-Hb),3.68(t,2H,Isoquinoline-H),3.78(s,3H,OMe),4.50(dd,J=11.0and 3.0Hz,1H,pyrazole,5-H),6.85-7.79(m,12H,ArH);13CNMR(CDCl3,125MHz):δ5.2,28.1,38.8,47.9,55.5,56.7,69.1,110.7,114.8,116.5,119.5,121.8,121.9,125.8,126.0,127.4,127.8,128.8,128.9,130.4,130.6,132.7,133.9,137.8,138.9,152.7,158.4,158.6,160.8.
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Linhong Jin et al..Synthesis, structure, and bioactivity of N"-substituted benzylidene-3,4,5-trimethoxybenzohydrazide and 3-acetyl-2-substituted phenyl-5-(3,4,5-trimethoxyphenyl)-2,3-dihydro-1,3,4-oxadiazole derivatives.《Bioorganic & Medicinal Chemistry Letters》.2006,第16卷第5036-5040页. |
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